Pharmaceutical composition comprising L- carnitine or alkanoyl L-carnitine for the prevention and treatment of diseases brought about by lipid metabolism disorders

ABSTRACT

A pharmaceutical compositions comprising L-carnitine or alkanoyl L-carnitine and hydroxycitric or pantothenic acid or derivatives thereof for the prevention and treatment of diseases brought about by lipid metabolism disorders, is disclosed.

[0001] The present invention relates to a novel therapeutic use ofL-carnitine, some alkanoyl L-carnitines and the pharmacologicallyacceptable salts thereof in combination with hydroxycitric orpantothenic acid or derivatives thereof (wherein “derivatives thereof”also encompasses natural products and their extracts containing same forthe prevention and therapeutic treatment of diseases brought about bylipid metabolism disorders, such as cardiovascular disorders,atherosclerosys, hyperlipidaemias and obesity, and for controlling anddecreasing the appetite.

[0002] According to its broadest aspect the invention relates to thecoordinated use of L-carnitine or an alkanoyl L-carnitine or thepharmacologically acceptable salts thereof with hydroxycitric orpantothenic acid or derivatives thereof. By “co-ordinated use” of theaforesaid compounds it is meant indifferently either theco-administration, i.e. the substantially concomitant supplementation ofL-carnitine or alkanoyl L-carnitine or a pharmacologically acceptablesalt thereof and hydroxycitric or pantothenic acid or a derivativethereof, as active ingredients, or the administration of a combinationpreparation comprising a mixture of the aforesaid active ingredients, inaddition to suitable excipients, if any.

[0003] The present invention also relates to orally, parenterally,rectally or transdermally administrable pharmaceutical compositionssuitable for treating the aforesaid disorders and for controlling anddecreasing the appetite, which comprise, as active ingredients,L-carnitine or an alkanoyl L-carnitine or a pharmacologically acceptablesalt thereof and hydroxycitric acid or pantothenic acid or derivativethereof. Preferred hydroxycitric acid derivatives are the salts andesters thereof and the natural products and their extracts containingsame, as specified in more detail hereinbelow. It should be understoodthat whenever in the present specification reference is made for thesake of simplicity to “hydroxycitric acid”, the naturally occurringcompound, i.e (−)-treo hydroxycitric acid, is meant.

[0004] Preferred pantothenic acid derivatives comprise4′-phosphopantothenate, 4′-phosphopantothenylcisteine,4′-phosphopantotheine, pantotheine and pantethine. Pantethine isparticularly preferred.

[0005] Hydroxycitric acid and derivatives thereof may occur as extractsof natural products containing hydroxycitric acid at highconcentrations, such as the extract of the fruits of Garcinia (Garciniacambodia, Garcinia atroviridis, Garcinia indica, Garcinia citrin), ofthe fruits of Malabar Tamarind or Gorikapuli (Lewis Y. L., NeelakantanS., Phyto-chemistry 4, 619, 1965), (Streenivasan A., Vankataraman R.,Current Science 4, 151, 1959) or other extract of natural productscontaining same.

[0006] A preferred salt of hydroxycitric acid is calcium hydroxycitrate.

[0007] The alkanoyl L-carnitines useful for the novel therapeutic use ofthe present invention are those wherein the alkanoyl group is a straightor branched group, having from 2 to 8 carbon atoms, preferably from 2 to6 carbon atoms Particularly preferred are acetyl, propionyl, butyryl,valeryl and isovaleryl L-carnitine.

[0008] Pharmaceutically acceptable salts of L-carnitine or alkanoylL-carnitine include, in addition to the inner salts, any salt of thesewith acids which do not give rise to undesired or side effects. Theformation of pharmaceutically acceptable acid addition salt is wellknown to the experts in pharmacy and pharmaceutical technology.

[0009] Non-limiting examples of suitable salts include the chloride,bromide, orotate, acid aspartate, acid citrate, acid phosphate,fumarate, acid fumarate, lactate, maleate, acid maleate, acid oxalate,acid sulfate, glucose phosphate, tartrate and acid tartrate salts.

[0010] Previous therapeutic uses of L-carnitine are already known.

[0011] For instance L-carnitine has been used in the cardiovascularfield in the treatment of acute and chronic myocardial ischaemia, anginapectoris, cardiac arrhythmias and insufficiency, and peripheral vasculardiseases.

[0012] In nephrology, L-carnitine has been administered to chronicuraemic patients who are subjected to regular haemodialysis treatmentwith a view to counteracting muscular asthenia and the onset of muscularcramps.

[0013] Moreover, U.S. Pat. No. 3,810,994 (Ethyl Corporation) disclosesthe therapeutic utility of pharmaceutical compositions of L-carnitine orsalts or esters thereof, for the treatment of obesity.

[0014] U.S. Pat. No. 4,255,449 (Cavazza) and U.S. Pat. No. 4,268,524(Cavazza) disclose the use of L-carnitine and alkanoyl L-carnitine tonormalize the abnormal ratio between low density lipoprotein (LDL)+ verylow density lipoproteins (VLDL) and high density lipoprotein (HDL) whichis an aetiological factor for various cardiovascular diseases.

[0015] As known, through the beta-oxidation of fatty acids L-carnitineis capable of preventing their accumulation and of supplying the energyrequirement of cells (Bremer Y., TIBS 2, 207, 1977) via modulation ofextra- and intramitochondrial CoA.

[0016] The carnitine pool not only regulates the bio-oxidation ofintramitochondrial fatty acids, but also inhibits the formation oftriglycerides (Bieber L. L., J. Biol. Chem. 254, 8163, 1979; Pande D.V., Proc. Nat. Acad. Sci. USA 72, 883, 1975).

[0017] Hydroxycitric acid, too, has for some time now been known as ametabolic factor. It is present, in fact, in large amounts in a numberof plants used as foodstuffs and, in particular, in Malabar Tamarind andin the fruits of various species of Garcinia and its extraction andisolation have permitted extensive biochemical and pharmacological studyof the substance. Recent data have revealed its importance as aregulator of the synthesis of cholesterol and fatty acids (Hamilton Y.G., Lipids 12, 1, 1976).

[0018] Hydroxycitric acid is capable of inhibiting the activity ofATP-citratolyase, an enzyme which catalyses the extramitochondrialconversion of citrates to oxoacetates and acetyl Coenzyme A.

[0019] The importance of this enzyme consists in its ability to maintainthe Coenzyme A pool necessary for lipid and cholesterol synthesis. Theenzymatic reaction catalysed by citratolyase which leads to thesynthesis of cholesterol and fatty acids from carbohydrates is inhibitedby hydroxycitric acid which together with the reduction in lipidsynthesis also leads to a greater storage of carbohydrates in the formof glycogen in the liver (Berkbout T. A., Biochem. J. 48, 6, 1990:Triscari Y., Sullivan A. C., Lipids 12, 357, 1976; Watson Y. A., FangM., Arch. Biochem. Biophys. 135, 209, 1969).

[0020] Both L-carnitine and hydroxycitric acid are, therefore, capableof exerting an action upon lipid metabolism via different mechanisms: onthe one hand, L-carnitine facilitates the oxidation andintramitochondrial utilization of fatty acids and prevents theaccumulation of triglycerides, and, on the other, hydroxycitric acidprevents their actual synthesis (Lowenstein Y. M., J. Biol. Chem. 246,629, 1971; Hood R. L., Comp. Biochemical Physiol. 81B, 667, 1985).

[0021] What have proved very surprising and unexpected, however, are thesynergistic effects which can be obtained on energy metabolism and onlipid metabolism by combining these two compounds or by coordinatelyadministering them.

[0022] This unexpected synergistic effect obtained by the co-ordinateduse of L-carnitine or its derivatives and hydroxycitric or pantothenicacid or derivatives thereof has been demonstrated in numerous studies,so much so, indeed, as to suggest that this combination can be used toadvantage in facilitating the elimination of lipids and cholesterol fromtissues, in the treatment of cardiovascular diseases, and in preventingabnormal formation and accumulation of fats.

[0023] The research conducted to date has shown that the coordinated useof the two compounds proves surprisingly effective in inhibiting theformation of atherosclerosis and the infiltration of tissues, as well asthe formation of cholesterol and triglycerides.

[0024] In addition to the anticholesterolaemic and antidyslipidaemiceffects induced by this combination, the research has also revealed areduction of appetite and reduced food consumption with consequentweight loss.

[0025] This new pharmaceutical composition can, therefore, be used inthe prevention and treatment of all those disease conditions related toa high concentration of cholesterol and lipids in the tissues, such as,for instance, atherosclerosis, hypercholesterolaemia, and cardiovasculardiseases, and in the treatment of obesity.

[0026] The toxicological results are reported below, as are the resultsof the most significant studies in terms of evidence of the surprisingsynergistic effect that can be obtained with a combination ofL-carnitine or one of its derivatives and hydroxycitric acid or one ofits derivatives. The data reported in these studies demonstrate theunexpected potentiation of action obtainable with this new compositionand that important practical applications stem from this activity in thepharmaceutical, dietary and alimentary fields for the prevention ortherapy of numerous disease conditions related to lipid metabolismdisorders, such as atherosclerosis, hypercholesterolaemia” obesity andcardiovascular diseases.

[0027] Toxicology

[0028] The tests performed, administering a combination of L-carnitineor its derivatives and calcium hydroxycitrate or an extract fromGarcinia cambogia (with a roughly 30% hydroxycitrate concentration) in asingle dose at high concentrations, have demonstrated the goodtolerability of the new composition. High doses of L-carnitine or itsderivatives (1 g/kg) could be administered, in fact, together with highdoses of calcium hydroxycitrate (up to and above 1 g/kg) or of Garciniacambogia hydroxycitrate extract (2 g/kg), orally to Wistar rats, withoutany evidence of signs of toxicity related to the administration of anyof the various presentation forms which the composition according to theinvention can take on. The good tolerability of the composition has alsobeen established through prolonged oral administration of the producttogether with the diet for three consecutive months in both male Wistarrats and in mice.

[0029] Tests in experimentally obese rats

[0030] Male Wistar rats aged about 2 months were fed on a lipogenic diet(50% glucose, 20% casein, 4% cellulose, 5% salt mixture, 1% hazel nutoil, 18% starch, 1% vitamin mixture).

[0031] This diet was administered for fifteen days consecutively todifferent groups of rats, one of which served as a control group,whereas in the other groups the diet was administered together withcalcium hydroxycitrate (1%-2%) or Garcinia cambogia extract (2%-4%) orL-carnitine (2%-4%) or acetyl L-carnitine or propionyl L-carnitine atthe same doses, or together with various combinations of these productsat the same doses. At the end of the fifteenth day of treatment, foodconsumption was evaluated in treated rats vs. controls and increases inbody weight and in serum triglycerides and epididymal fat were measured.

[0032] Food consumption results

[0033] During the fifteen days of treatment on a lipogenic diet asubstantial reduction in daily food consumption was detected in theanimals treated with calcium hydroxycitrate or with Garcinia cambogiaextract. No changes compared to controls were noted, on the other hand,in rats treated with L-carnitine, propionyl L-carnitine or acetylL-carnitine. The reduction in food consumption was, however, much moremarked in the group of animals treated with the combination of calciumhydroxycitrate plus L-carnitine, acetyl L-carnitine, and particularlypropionyl L-carnitine, even as compared to that detected in the ratstreated with calcium hydroxycitrate or Garcinia cambogia extract.

[0034] Whereas, with the largest dose of calcium hydroxycitrate, thedaily food consumption dropped from an initial values of 18.8 g to avalue of 15.1 g after fifteen days' treatment, the respective values forthe lower dose were 19.2 g and 17.1 g.

[0035] The non-significant changes detected with the two doses ofL-carnitine, acetyl L-carnitine and propionyl L-carnitine become highlysignificant when these products are combined even with the lower dosesof calcium hydroxycitrate or Garcinia cambogia extract.

[0036] In the animals treated with the combination of calciumhydroxycitrate and propionyl L-carnitine at the lower doses, this leads,for example, to a reduction in food consumption from 18.4 g to 13.2 g,thus demonstrating a potentiation of the effect on the reduction of foodintake. A similar, though more limited, degree of potentiation isobserved in the data for the combination of the various carnitines withGarcinia cambogia extract (Table 1).

[0037] Body weight results

[0038] Body weight gain is also reduced by the administration of calciumhydroxycitrate in correlation with the dose administered. In thesetests, too, while no significant changes are detectable with theadministration of carnitines alone, highly significant changes areobserved when the carnitines are combined with calcium hydroxcitrate orwith Garcinia cambogia extract. In the group of animals treated with thecombination of calcium hydroxycitrate plus carnitines, the reduction inbody weight gain is much greater than that obtainable withadministration of the highest dose of calcium hydroxycitrate alone(Table 2).

[0039] Serum triglyceride and epididymal fat results

[0040] The potent synergistic effect between carnitines and calciumhydroxycitrate or Garcinia cambogia extract is clearly demonstrated bythe results regarding serum triglyceride and epididymal fat values inrats on a lipogenic diet. After fifteen days of treatment a powerfuleffect in terms of a reduction in both parameters was detectable, infact, in the group of animals treated with the combination of carnitinesplus calcium hydroxycitrate or Garcinia cambogia extract.

[0041] Among the carnitines, the most effective was propionylL-carnitine, which, when combined with calcium hydroxycitrate, maintainsboth serum triglycerides and epididymal fats practically within normallevels (Table 3).

[0042] Experimental hypertrigyceridaemia tests

[0043] In these tests, male Wistar rats serum triglyceride elevation wasinduced experimentally by means of the oral administration of fructoseaccording to the method disclosed by L. A. V. Carlson (J. Atheroscler.Res. 8, 667, 1968; Atherosclerosis 16, 349, 1972). In the 5-day periodprior to administration of 3 g of fructose, the rats, divided intogroups, were treated with L-carnitine or its derivatives or with calciumhydroxycitrate or Garcinia cambogia extract at different doses, or withvarious combinations of these products.

[0044] The administration of these products was then repeated two hoursafter administration of fructose, and 5 hours later all animals weresacrificed. Triglyceride assay was then performed according to themethod of R. K. Donabedian (Clin. Chem 20, 632, 1974). The resultsobtained in these tests demonstrate that the fructose-inducedhypertriglyceridaemia is not modified by the administration ofcarnitines, whereas it is reduced by the administration of calciumhydroxycitrate or Garcinia cambogia extract. Thehypertriglyceridaemia-reducing effect is, however, substantiallyincreased and potentiated when the calcium hydroxycitrate or Garciniacambogia extract is combined with the carnitines. The potentiatingeffect is marked for all carnitines, but most notably in the case ofpropionyl L-carnitine.

[0045] Experimental atherosclerosis tests

[0046] Also in atherosclerotic vascular lesions induced experimenatllyaccording to the method of M. R. Malinow (Atherosclerosis 48, 105,1983), with administration of an atherogenic diet (24% casein, 10%cotton oil, 5% salt, 60% sugar, 1% cholesterol, Vit D₂ 200 mUST/g ofdiet) for six weeks consecutively to different groups of male Wistarrats, it has been shown that the combination of carnitines plus calciumhydroxycitrate or Garcinia cambogia extract is capable of substantiallypotentiating the anti-atherogenic effect.

[0047] This was assessed by measuring the thickness of the abdominalaorta and the intensity of staining induced by Sudan IV using a scoringsystem from 1 to 5, according to degree of severity. By means of thisassessment, it was clearly demonstrated that both L-carnitine andcalcium hydroxycitrate or Garcinia cambogia extract are capable ofreducing the severity of the atherosclerotic lesions. The incidence ofthese lesions, however, is substantially inhibited to the point ofcomplete elimination in the groups of animals treated with a combinationof these products.

[0048] The incidence of atherosclerotic lesions was completely inhibitedparticularly with the combination of calcium hydroxycitrate andpropionyl L-carnitine. These tests, too, therefore, demonstrate theintense synergistic action of carnitines and calcium hydroxycitrate.

[0049] Experimental hypercholesterolaemia tests

[0050] The results of tests conducted in Wistar rats withhypercholesterolaemia induced by diet according to the method describedby C. R. Sirtori (Atherosclerosis 26, 78, 1977) also confirm thesurprisingly marked potentiating effect of calcium hydroxycitrate pluscarnitines in reducing cholesterol values. Treatment both withL-carnitine and with calcium hydroxycitrate or with Garcinia cambogiaextract, or with a combination of these products, was initiated togetherwith a hypercholesterolaemia-inducing diet and continued for six weeksconsecutively. At the end of this period, the assay was performed on theserum of the control animals and on that of the treated animalsaccording to the method described by P. Roschlan (Clin. Chem. Clin.Biochem. 12, 403, 1975). The total cholesterol values observed showed afair degree of lowering induced both by the treatment with calciumhydroxycitrate and by the treatment with Garcinia cambogia extract.Practically normal cholesterolaemia values were restored in the animalstreated with the combination of calcium hydroxycitrate plus carnitines,thus demonstrating a marked synergistic effect between these twocompounds characterizing the novel composition according to the presentinvention.

[0051] The following non-limiting examples illustrate some compositionsaccording to the present invention.

EXAMPLES

[0052] 1) L-carnitine mg 500 Calcium hydroxycitrate mg 300 2) AcetylL-carnitine mg 500 Calcium hydroxycitrate mg 300 3) PropionylL-carnitine mg 500 Calcium hydroxycitrate mg 300 4) IsovalerylL-carnitine mg 500 Calcium hydroxycitrate mg 300 5) Valeryl L-carnitinemg 500 Calcium hydroxycitrate mg 300 6) Butyryl L-carnitine mg 500Calcium hydroxycitrate mg 300 7) L-carnitine mg 500 Garcinia cambodiaextract mg 500 (30% hydroxycitric acid) 8) Acetyl L-carnitine mg 500Garcinia cambodia extract mg 500 (30% hydroxycitric acid) 9) PropionylL-carnitine mg 500 Garcinia cambodia extract mg 500 (30% hydroxycitricacid) 10) Isovaleryl L-carnitine mg 500 Garcinia cambodia extract mg 500(30% hydroxycitric acid) 11) Valeryl L-carnitine mg 500 Garciniacambodia extract mg 500 (30% hydroxycitric acid) 12) Butyryl L-carnitinemg 500 Garcinia cambodia extract mg 500 (30% hydroxycitric acid) 13)L-carnitine 500 mg, calcium hydroxycitrate 300 mg, Beta carotene 12500I.V., Vit. B₂ 15 mg, Vit. C 100 mg. Vit. D₃ 200 I.V., Vit. B₁₂ 1.5 mcg,Folic acid 200 mcg, Vit. E 10 mg, Iron (as FeSO₄) 32 mg, Manganese (asMnSO₄) 5 mg, Zinc (as Zn acetate) 5 mg, Phosphorus (as Na₂HPO₄) 25 mg,Molybdenum 7,5 mg, Potassium 7,5 mg, Chromium 15 mcg, Selenium 40 mcg.14) L-carnitine g 1.223 pantethine g 0.500 methyl-p-hydroxybenzoate g0.015 sorbitol g 1.000 sodium saccharinate g 0.060 citric acid g 0.120sodium hydroxyde g 0.032 bigarade flavour g 0.050 orange flavour g 0.010pure water, balance to ml 10.0

[0053] TABLE I MEAN DAILY FOOD CONSUMPTION (g) PER ANIMAL Beforetreatment After 15 days Calcium hydroxycitrate 19.2 ± 0.65 17.1 ± 0.35(g 1/100 g diet) Calcium hydroxycitrate 18.8 ± 0.44 15.1 ± 0.46 (g 2/100g diet) L-carnitine 17.3 ± 0.35 181.1 ± 0.50  (g 2/100 g diet)L-carnitine 18.4 ± 0.61 17.8 ± 0.41 g 4/100 g diet) Acetyl L-carnitine18.6 ± 0.39 18.4 ± 0.44 (g 2/100 g diet) Acetyl L-carnitine 18.2 ± 0.4118.8 ± 0.57 (g 4/100 g diet) Propionyl L-carnitine 17.7 ± 0.56 17.1 ±0.38 (g 2/100 g diet) Poprionyl L-carnitine 18.2 ± 0.44 18.5 ± 0.48 (g4/100 g diet) Garcinia cambodia 17.9 ± 0.34 16.8 ± 0.44 (g 4/ 100 gdiet) Calcium hydroxycitrate 18.9 ± 0.61 14.4 ± 0.50 (g 1/100 g diet) +L-carnitine (g 2/100 g diet) Calcium hydroxycitrate 19.1 ± 0.58 14.8 ±0.64 (g 1/100 g diet) + Acetyl L-carnitine (g 2/100 g diet) Calciumhydroxycitrate 18.4 ± 0.49 13.2 ± 0.53 (g 1/100 g diet) + PropionylL-carnitine (g 2/100 g diet) L-carnitine 18.1 ± 4.7  15.9 ± 4.1  (g2/100 g diet) + Garcinia cambodia (g 4/100 g diet) Acetyl L-carnitine18.8 ± 3.9  16.2 ± 4.9  (g 2/100 g diet) + Garcinia cambodia (g 4/100 gdiet) Propionyl L-carnitine 18.1 ± 4.8  14.4 ± 4.7  (g 2/100 g diet) +Garcinia cambodia (g 4/100 g diet)

[0054] TABLE 2 BODY WEIGHT INCREASE AFTER 15 DAY-TREATMENT Final bodyweight increase (g) Controls 62.8 ± 3.5 Calcium hydroxycitrate 46.6 ±4.1 (g 1/100 g diet) Calcium hydroxycitrate 38.9 ± 3.8 (g 2/100 g diet)L-carnitine 66.2 ± 4.9 (g 2/100 g diet) L-carnitine 64.5 ± 5.1 (g 4/100g diet) Acetyl L-carnitine 60.4 ± 7.1 (g 2/100 g diet) AcetylL-carnitine 60.1 ± 6.1 (g 4/100 g diet) Propionyl L-carnitine 62.4 ± 3.9(g 2/100 g diet) Poprionyl L-carnitine 58.7 ± 3.7 (g 4/100 g diet)Garcinia cambodia 51.4 ± 3.3 (g 4/100 g diet) Calcium hydroxycitrate28.7 ± 4.4 (g 1/100 g diet) + L-carnitine (g 2/100 g diet) Calciumhydroxycitrate 31.6 ± 3.9 (g 1/100 g diet) + Acetyl L-carnitine (g 2/100g diet) Calcium hydroxycitrate 24.4 ± 2.8 (g 1/100 g diet) + PropionylL-carnitine (g 2/100 g diet) L-carnitine 38.6 ± 3.1 (g 2/100 g diet) +Garcinia cambodia (g 4/100 g diet) Acetyl L-carnitine 36.8 ± 4.4 (g2/100 g diet) + Garcinia cambodia (g 4/100 g diet Propionyl L-carnitine34.8 ± 6.5 (g 2/100 g diet) + Garcinia cambodia (g 4/100 g diet)

[0055] TABLE 3 SERUM TRIGLYCERIDES AND EPIDIDIMAL FAT AFTER 15DAY-TREATMENT Triglycerides Epididimal fat (mg/100 ml) (g) Controls94.68 ± 6.6 4.65 ± 0.41 Calcium hydroxycitrate 76.84 ± 6.9 3.91 ± 0.36(g 1/100 g diet) Calcium hydroxycitrate 73.66 ± 7.1 3.32 ± 0.39 (g 2/100g diet) L-carnitine 92.55 ± 7.7 4.21 ± 4.1 (g 2/100 g diet) L-carnitine90.44 ± 6.8 4.34 ± 2.9 (g 4/100 g diet) Acetyl L-carnitine 95.81 ± 8.24.10 ± 3.8 (g 2/100 g diet) Acetyl L-carnitine  90.8 ± 7.5 4.15 ± 3.5 (g4/100 g diet) Propionyl L-carnitine  88.4 ± 8.16 4.19 ± 4.4 (g 2/100 gdiet) Poprionyl L-carnitine  82.7 ± 6.6 4.0 ± 5.6 (g 4/100 g diet)Garcinia cambodia  80.4 ± 7.3 3.85 ± 3.5 (g 4/100 g diet) Calciumhydroxycitrate  71.5 ± 6.7 3.25 ± 2.9 (g 1/100 g diet) + L-carnitine (g2/100 g diet) Calcium hydroxycitrate  68.2 ± 5.5  3.0 ± 2.7 (g 1/100 gdiet) + Acetyl L-carnitine (g 2/100 g diet) Calcium hydroxycitrate  60.5± 7.4 2.25 ± 2.2 (g 1/100 g diet) + Propionyl L-carnitine (g 2/100 gdiet) L-carnitine  75.4 ± 3.1 3.50 ± 3.1 (g 2/100 g diet) + Garciniacambodia (g 4/100 g diet) Acetyl L-carnitine  72.3 ± 4.4 3.25 ± 4.3 (g2/100 g diet) + Garcinia cambodia (g 4/100 g diet Propionyl L-carnitine 70.3 ± 5.6 2.95 ± 3.8 (g 2/100 g diet) + Garcinia cambodia (g 4/100 gdiet)

[0056] TABLE 4 TEST ON EXPERIMENTALLY-INDUCED HYPERTRIGYCERIDAEMIA(mg/100 ml) Controls 195.8 ± 9.8 Calcium hydroxycitrate 170.6 ± 8.5 (g0.5/Kg) Calcium hydroxycitrate 145.5 ± 8.5 (g 1/Kg) L-carnitine 190.4 ±9.6 (g 0.5/Kg) L-carnitine 190.8 ± 8.6 (g 1/Kg) Acetyl L-carnitine 191.2± 9.1 (g 0.5/Kg) Acetyl L-carnitine 188.4 ± 5.5 (g 1/Kg) PropionylL-carnitine 184.2 ± 6.8 (g 0.5/Kg) Poprionyl L-carnitine 180.4 ± 7.9 (g1/Kg) Garcinia cambodia 170.6 ± 5.4 (g 0.5/Kg) Calcium hydroxycitrate125.8 ± 9.1 (g 0.5/Kg) + L-carnitine (g 0.5/Kg) Calcium hydroxycitrate120.4 ± 8.8 (g 0.5/Kg) + Acetyl L-carnitine (g 0.5/Kg) Calciumhydroxycitrate   108 ± 9.4 (g 0.5/Kg) + Propionyl L-carnitine (g 0.5/Kg)Garcinia cambodia 145.4 ± 8.6 (g 0.5/Kg) + L-carnitine (g 0.5/Kg)Garcinia cambodia 140.4 ± 7.4 (g 0.5/Kg) + Acetyl L-carnitine (g 0.5/Kg)Garcinia cambodia   125 ± 8.5 (g 0.5/Kg) + Propionyl L-carnitine (g0.5/Kg)

[0057] TABLE 5 TESTS ON EXPERIMENTALLY-INDUCED HYPERCHOLESTEROLEMIA(TOTAL CHOLESTEROL mg/dl) Controls  92.5 ± 4.4 Hypercholesterolemiccontrols 270.5 ± 10.4 Calcium hydroxycitrate 196.6 ± 9.6 (g 1/100 gdiet) Calcium hydroxycitrate 180.5 ± 8.1 (g 2/100 g diet) L-carnitine270.4 ± 5.1 (g 2/100 g diet) L-carnitine 260.6 ± 4.4 (g 4/100 g diet)Acetyl L-carnitine 266.7 ± 7.7 (g 2/100 g diet) Acetyl L-carnitine 255.4± 9.4 (g 4/100 g diet) Propionyl L-carnitine 250.6 ± 10.1 (g 2/100 gdiet) Poprionyl L-carnitine 235.3 ± 9.6 (g 4/100 g diet) Garciniacambodia 250.7 ± 4.7 (g 4/100 g diet) Calcium hydroxycitrate 155.8 ± 8.8(g 1/100 g diet) + L-carnitine (g 2/100 g diet) Calcium hydroxycitrate150.5 ± 7.1 (g 1/100 g diet) + Acetyl L-carnitine (g 2/100 g diet)Calcium hydroxycitrate 110.6 ± 6.6 (g 1 100 g diet) + PropionylL-carnitine (g 2/100 g diet) L-carnitine 179.6 ± 9.6 (g 2/100 g diet) +Garcinia cambodia (g 4/100 g diet) Acetyl L-carnitine 165.9 ± 8.9 (g2/100 g diet) + Garcinia cambodia (g 4/100 g diet Propionyl L-carnitine155.5 ± 6.8 (g 2/100 g diet) + Garcinia cambodia (g 4/100 g diet)

1. An orally, parenterally, rectally or transdermally administrablepharmaceutical composition for treating cardiovascular, thromboembolic,atherosclerotic, hyperlipidemic disorders and obesity and for decreasingappetite, comprising L-carnitine or an alkanoyl L-carnitine wherein thealkanoyl group is a straight or branched alkanoyl having 2-8, preferably2-6, carbon atoms or a pharmacologically acceptable salt thereof, andhydroxycitric acid or pantothenic acid or derivative thereof as activeingredients, and a pharmacologically acceptable excipient.
 2. Thecomposition of claim 1 , wherein the alkanoyl group is selected fromacetyl, propionyl, butyryl, valeryl and isovaleryl.
 3. The compositionof claims 1 or 2, wherein the hydroxycitric acid derivative is a salt orester thereof, a natural product or extract thereof containing same. 4.The composition of claims 1 or 2, wherein the pantothenic acidderivative is selected from the group comprising 4′-phosphopantothenate,4′-phosphopantothenylcisteine, 4′-phosphopantotheine, pantotheine andpantethine.
 5. The composition of claim 3 , wherein the hydroxycitricacid derivative is calcium hydroxycitrate.
 6. The composition of claim 3, wherein said extract is the extract from the fruits of Garcinia(Garcinia cambodia, Garcinia atroviridis, Garcinia indica, Garciniacitrin), or Malabar Tamarind or gorikapuli.
 7. The composition of anyoneof the preceding claims, wherein the weight ratio between hydroxycitricacid or derivative thereof and L-carnitine, alkanoyl L-carnitine orpharmacologically acceptable salt thereof is from 1:1 to 1:100, andwherein the weight ratio between pantothenic acid or derivative thereofand L-carnitine, alkanoyl L-carnitine or pharmacologically acceptablesalt thereof is from 10:1 to 1:100.
 8. The composition of anyone of thepreceding claims which further comprises vitamins, mineral salts,antioxidants and vegetal fibers.
 9. The composition of anyone of thepreceding claims in a solid, semisolid, liquid, semiliquid, powder,granular or liposomic form, as tablets, capsules, granulates, powdersand vials suitable for oral, parenteral, rectal or topic administration.10. Co-ordinated use of L-carnitine or alkanoyl L-carnitine wherein thealkanoyl group has 2-8, preferably 2-6, carbon atoms, orpharmacologically acceptable salt thereof, and hydroxycitric acid orpantothenic acid or derivative thereof for treating cardiovascular,thromboembolic, atherosclerotic, hyperlipidaemic disorders and obesity,and for controlling and decreasing the appetite.